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1 august 2010 - Press release

A new antibody-producing molecular mechanism has been identified which could be key to lupus or rheumatoid arthritis

The study is published in the prestigious journal Nature Immunology

An international team, led by the IMIM (Hospital del Mar Research Institute) and the Mount Sinai School of Medicine in New York, has identified a new molecular mechanism for the production of antibodies by B-lymphocytes. This finding opens the door to new treatments for autoimmune diseases, such as lupus and rheumatoid arthritis, and perhaps tumors of the immune system such as lymphoma and multiple myeloma.

The IMIM B-Cell Research Group led by Andrea Cerutti, an ICREA Research Professor, has discovered a new mechanism for the activation of B-lymphocytes by molecules known as BAFF and APRIL. These molecules promote the interaction of the signal protein MyD88 with TACI, a receptor that stimulates the activation of B-lymphocytes and the production and diversification of antibodies. Of note, MyD88 is a signal protein that is not usually involved in the activation of B-lymphocytes, but is rather needed by cells of the innate immune system to sense the presence of pathogens.

The diversification and plasticity of the immune system are essential for achieving adequate immune protection. The interaction between TACI and MyD88 described in this study unveils an unexpected new link between the innate and adaptive immune systems. The TACI-MyD88 interaction would augment the efficacy of our immune system by increasing its plasticity. According to Raul Santamaria, a member of the IMIM B-Cell Research Group and co-first author of this study: “The importance of this work relates to the discovery of the interaction between TACI and MyD88, a connection that was until now unknown and that would make our antibody responses more efficient. The identification of this interaction may lead to the development of new therapeutics against diseases associated with exaggerated activation of B-lymphocytes by BAFF and APRIL.”

When talking about the immune system, we must differentiate between the innate immune system and the adaptive immune system. The innate immune system is an ancestral immune defense “protocol” that is encoded in us from birth and that has remained highly conserved throughout the evolutionary history of all living organisms. This innate protocol recognizes and combats pathogens by means of relatively unsophisticated defensive molecules, some of which utilize the signal protein MyD88. Paradoxically, even though we can suffer from a failure of the innate immune system, for example in diseases such as lupus, there has not been a lot of research carried out in this area. The adaptive immune system, however, is the one that combats pathogens in a more specific manner, by means of highly sophisticated defensive molecules such as the antibodies produced by B-lymphocytes (an example of antibodies are those induced by vaccinations). Although generally exerting a protective role, B-lymphocytes can precipitate or exacerbate lupus and rheumatoid arthritis, two autoimmune disorders associated with exaggerated production of BAFF and APRIL and abnormally strong signals from TACI. Lupus and rheumatoid arthritis cause inflammation and tissue damage through various mechanisms, including production of aberrant antibodies (called autoantibodies) that react against components of our own body instead of fighting against pathogens.

“The discovery of how TACI interacts with MyD88 opens the door to the design of new drugs capable of blocking this interaction at a molecular level, making it possible to mitigate the production of harmful antibodies such as those released by autoreactive B-lymphocytes in patients with autoimmune disease. Drugs switching off TACI-MyD88 interaction might be also beneficial to attenuate the growth of B-lymphocyte-derived tumors such as lymphoma and multiple myeloma”, explains Irene Puga, another member of the IMIM B-Cell Research Group involved in this study.

This research, which was carried out using B-lymphocytes and tissues from patients carrying TACI and MyD88 mutations and from genetically engineered mice lacking MyD88, brings new data to studies previously published y other groups and performed on BAFF-transgenic mice and offers specific knowledge needed to create new drugs. “Autoimmune disorders, such as lupus or rheumatoid arthritis, are extremely incapacitating and prevalent diseases for which there is still no cure. Findings such as these may lead to the identification of new therapeutic molecules that could mitigate the secondary effects associated with current treatment protocols”, concludes Andrea Cerutti.

Reference article:

B He, R Santamaria, W Xu, M Cols, K Chen, I Puga, M Shan, H Xiong, J B Bussel, A Chiu, A Puel, J Reichenbach, L Marodi, R Döffinger, J Vasconcelos, A Issekutz, J Krause, G Davies, X Li, B Grimbacher, A Plebani, E Meffre, C Picard, C Cunningham-Rundles, JL Casanova & A Cerutti.“The transmembrane activator TACI triggers immunoglobulin class switching by activating B cells through the adaptor MyD88” Nature Immunology. DOI 10.1038/ni.1914

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